Piperidine/piperazine-type inhibitors of p38 kinase

ABSTRACT

The invention is directed to inhibition of p38-α kinase using compounds of the formula  
                 
 
     and the pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, wherein:  
     Ar 1  is an aryl group substituted with 0-5 non-interfering substituents, wherein two adjacent noninterfering substituents can form a fused aromatic or nonaromatic ring;  
     L 1  and L 2  are linkers;  
     each R 1  is independently a noninterfering substituent;  
     Z 1  is CR 2  or N wherein R 2  is hydrogen or a noninterfering substituent;  
     m is 0-4;  
     each of n and p is an integer from 0-2 wherein the sum of n and p is 0-3;  
     Ar 2  is a substantially planar, monocyclic or polycyclic aromatic moiety having one or more optional ring heteroatoms, said moiety being optionally substituted with one or more non-interfering substituents, two or more of which may form a fused ring;  
     Z is —W i —COX j Y wherein Y is COR 3  or an isostere thereof; R 3  is a noninterfering substituent, each of W and X is a spacer of 2-6 Å, and each of i and j is independently 0 or 1;  
     wherein the smallest number of covalent bonds in the compound separating the atom of Ar 1  bonded to L 2  to the atom of Ar 2  bonded to L 1  is at least 6, where each of said bonds has a bond length of 1.2 to 2.0 angstroms; and/or wherein the distance in space between the atom of Ar 1  bonded to L 2  and the atom of Ar 2  bonded to L 1  is 4.5-24 angstroms;  
     with the proviso that the portion of the compound represented by Ar 2 —Z is not  
                 
 
      wherein  represents a single or double bond; n is 0-3; one Z 2  is CA or CRA and the other is CR, CR 2 , NR or N; A is —W i —COX j Y wherein Y is COR or an isostere thereof, each of W and X is a spacer of 2-6 Å, and each of i and j is independently 0 or 1; Z 3  is NR or O; and each R is independently hydrogen or a noninterfering substituent.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. §119(e) fromU.S. Ser. No. 60/252,196 filed Nov. 20, 2000.

FIELD OF THE INVENTION

[0002] The invention relates to treating various disorders associatedwith enhanced activity of kinase p38-α. More specifically, it concernspiperadine and piperazine derivatives useful in these methods.

BACKGROUND ART

[0003] A large number of chronic and acute conditions have beenrecognized to be associated with perturbation of the inflammatoryresponse. A large number of cytokines participate in this response,including IL-1, IL-6, IL-8 and TNF. It appears that the activity ofthese cytokines in the regulation of inflammation rely at least in parton the activation of an enzyme on the cell signaling pathway, a memberof the MAP kinase family generally known as p38 and alternatively knownas CSBP and RK. This kinase is activated by dual phosphorylation afterstimulation by physiochemical stress, treatment with lipopolysaccharidesor with proinflammatory cytokines such as IL-1 and TNF. Therefore,inhibitors of the kinase activity of p38 are useful anti-inflammatoryagents.

[0004] Eye diseases associated with a fibroproliferative conditioninclude retinal reattachment surgery accompanying proliferativevitreoretinopathy, cataract extraction with intraocular lensimplantation, and post glaucoma drainage surgery.

[0005] PCT applications WO98/06715, WO98/07425, and WO 96/40143, all ofwhich are incorporated herein by reference, describe the relationship ofp38 kinase inhibitors with various disease states. As mentioned in theseapplications, inhibitors of p38 kinase are useful in treating a varietyof diseases associated with chronic inflammation. These applicationslist rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, goutyarthritis and other arthritic conditions, sepsis, septic shock,endotoxic shock, Gram-negative sepsis, toxic shock syndrome, asthma,adult respiratory distress syndrome, stroke, reperfusion injury, CNSinjuries such as neural trauma and ischemia, psoriasis, restenosis,cerebral malaria, chronic pulmonary inflammatory disease, silicosis,pulmonary sarcosis, bone resorption diseases such as osteoporosis,graft-versus-host reaction, Crohn's Disease, ulcerative colitisincluding inflammatory bowel disease (IBD) and pyresis.

[0006] The above-referenced PCT applications disclose compounds whichare p38 kinase inhibitors said to be useful in treating these diseasestates. These compounds are either imidazoles or are indoles substitutedat the 3- or 4-position with a piperazine ring linked through acarboxamide linkage. Additional compounds which are conjugates ofpiperazines with indoles are described as insecticides in WO97/26252,also incorporated herein by reference.

[0007] Certain aroyl/phenyl-substituted piperazines and piperidineswhich inhibit p38-α kinase are described in PCT publication WO00/12074published Mar. 9, 2000. In addition, indolyl substituted piperidines andpiperazines which inhibit this enzyme are described in PCT publicationNo. WO99/61426 published Dec. 2, 1999. Carbolene derivatives ofpiperidine and piperazine as p38-α inhibitors are described inPCT/US00/07934 filed Mar. 24, 2000.

[0008] None of the foregoing patents describes the piperadine typederivatives described herein which specifically inhibit p38-α.

SUMMARY OF THE INVENTION

[0009] The invention is directed to methods and compounds useful intreating conditions that are characterized by enhanced p38-α activity.These conditions include inflammation, proliferative diseases, andcertain cardiovascular disorders as well as Alzheimer's disease asfurther described below. Compounds of the invention inhibit p38 kinase,the α-isoform in particular, and are thus useful in treating diseasesmediated by these activities. The compounds of the invention are of theformula (1):

[0010] and the pharmaceutically acceptable salts thereof, or apharmaceutical composition thereof, wherein:

[0011] Ar¹ is an aryl group substituted with 0-5 non-interferingsubstituents, wherein two adjacent noninterfering substituents can forma fused aromatic or nonaromatic ring;

[0012] L¹ and L² are linkers;

[0013] each R¹ is independently a noninterfering substituent;

[0014] Z¹ is CR² or N wherein R² is hydrogen or a noninterferingsubstituent;

[0015] mis 0-4;

[0016] each of n and p is an integer from 0-2 wherein the sum of n and pis 0-3;

[0017] Ar² is a substantially planar, monocyclic or polycyclic aromaticmoiety having one or more optional ring heteroatoms, said moiety beingoptionally substituted with one or more non-interfering substituents,two or more of which may form a fused ring;

[0018] Z is —W₁—COX_(j)Y wherein Y is COR³ or an isostere thereof; R³ isa noninterfering substituent, each of W and X is a spacer of 2-6 Å, andeach of i and j is independently 0 or 1;

[0019] wherein the smallest number of covalent bonds in the compoundseparating the atom of Ar¹ bonded to L² to the atom of Ar² bonded to L¹is at least 6, where each of said bonds has a bond length of 1.2 to 2.0angstroms; and/or wherein the distance in space between the atom of Ar¹bonded to L² and the atom of Ar² bonded to L¹ is 4.5-24 angstroms;

[0020] with the proviso that the portion of the compound represented byAr²—Z is not

[0021]  wherein

represents a single or double bond; n is 0-3; one Z²is CA or CRA and theother is CR, CR₂, NR or N; A is —W_(i)—COX_(j)Y wherein Y is COR or anisostere thereof, each of W and X is a spacer of 2-6 Å, and each of iand j is independently 0 or 1; Z³ is NR or O; and each R isindependently hydrogen or a noninterfering substituent.

[0022] The invention is further directed to methods of treatinginflammation or proliferative conditions using these compounds. Theinvention is also directed to treating conditions associated withcardiac failure and Alzheimer's disease using the invention compounds.

DETAILED DESCRIPTION

[0023] The compounds of formula (1) are useful in treating conditionswhich are characterized by overactivity of p38 kinase, in particular theα-isoform. Conditions “characterized by enhanced p38-α activity” includethose where this enzyme is present in increased amount or wherein theenzyme has been modified to increase its inherent activity, or both.Thus, “enhanced activity” refers to any condition wherein theeffectiveness of these proteins is undesirably high, regardless of thecause.

[0024] The compounds of the invention are useful in conditions wherep38-α kinase shows enhanced activity. These conditions are those inwhich fibrosis and organ sclerosis are caused by, or accompanied by,inflammation, oxidation injury, hypoxia, altered temperature orextracellular osmolarity, conditions causing cellular stress, apoptosisor necrosis. These conditions include ischemia-reperfusion injury,congestive heart failure, progressive pulmonary and bronchial fibrosis,hepatitis, arthritis, inflammatory bowel disease, glomerular sclerosis,interstitial renal fibrosis, chronic scarring diseases of the eyes,bladder and reproductive tract, bone marrow dysplasia, chronicinfectious or autoimmune states, spinal chord injury and traumatic orsurgical wounds. These conditions, of course, would be benefited bycompounds which inhibit p38-α. Methods of treatment with the compoundsof the invention are further discussed below.

[0025] The compounds useful in the invention are derivatives ofpiperadine/piperazine-type compounds containing a mandatory substituent,Z attached to the aromatic moiety Ar² The aromatic moiety is asubstantially planar, monocyclic or polycyclic aromatic moiety havingone or more optional ring heteroatoms. The aromatic moiety may beoptionally substituted with one or more non-interfering substituents,two or more of which may form a fused ring.

[0026] In somewhat greater detail the aromatic moiety Ar² comprises anoptionally substituted monocyclic or polycyclic aromatic nucleus,wherein the aromatic nucleus consists of a carbocyclic or heterocyclicring selected from (i) a five-membered heterocyclic or carbocyclic ring(ii) a six-membered carbocyclic or heterocyclic ring; (iii) afive-membered carbocyclic or heterocyclic ring fused to anotherfive-membered carbocyclic or heterocyclic ring; (iv) a six-memberedcarbocyclic or heterocyclic ring fused to another six-memberedcarbocyclic or heterocyclic ring; and (v) a five-membered heterocyclicor carbocyclic ring fused to a six-membered carbocyclic or heterocyclicring. Examples of the foregoing include the following aromatic moieties:

[0027] where R is a noninterfering substituent.

[0028] Particular examples of Ar² in formula (1) are such that theportion of compound (1) represented by L¹—Ar²—Z is selected from thefollowing:

[0029] wherein n is 0, 1 or 2; X¹ is NR, CR₂, O or S; and each R isindependently H or a noninterfering substituent; and two or more Rgroups may form a fused ring;

[0030] wherein n is 0-4; R is H or a noninterfering substituent wheretwo or more R groups may form a fused ring; and one or more ring carbonsmay be optionally replaced with nitrogen;

[0031] wherein each n is inpendently 0 to 3; R is H or a noninterferingsubstituent, where two or more R groups may form a fused ring; and oneor more ring carbons may be optionally replaced with nitrogen;

[0032] wherein, subject to the proviso set forth above with respect toformula (1), one B is L¹ and the other is Z; wherein a is 0 to 4 suchthat the positions on the six membered rings (1) and (3) to which(R)_(a) is bonded can include X² when X² is C; b is 0-3 such that thepositions on the five-membered rings (2) and (4) to which (R)_(b) isbonded can include X² and X¹, when X² is C and X¹ is N or C; each X² isindependently N or CR; X¹ is NR, CR₂, O or S; each R is H or anoninterfering substituent where two or more R groups may form a fusedring; wherein one or more of the ring carbons that are at positionsother than X² or X¹ and that are also not bound to B can be optionallyreplaced with N;

[0033] wherein one B is L¹ and the other is Z; a is 0-4 such that thepositions on the rings (1) and (3) to which (R)_(a) can be bondedinclude X² and X¹ where X² is C and X¹ is C or N; b is 0 or 3 such thatthe positions on the rings (2) and (4) to which (R)_(b) can be bondedinclude X¹, X² and X³ when X¹ is C or N and X² and/or X³ are C; each X¹is independently NR, C(R)₂, O or S; X² and X³ are independently N or CR;each R is independently H or a noninterfering substituent where two ormore R groups can optionally form a fused ring; wherein one or more ofthe ring carbons that are at positions other than X¹, X² or X³, and thatare also not bound to B, can be optionally replaced with N.

[0034] Certain positions of the molecule of formula I are described aspermitting “noninterfering substituents.” This terminology is usedbecause the substituents in these positions generally speaking are notrelevant to the essential activity of the molecule taken as a whole. Awide variety of substituents can be employed in these positions, and itis well within ordinary skill to determine whether any particulararbitrary substituent is or is not “noninterfering.”

[0035] As used herein, a “noninterfering substituent” is a substituentwhich leaves the ability of the compound of formula (1) to inhibit p38-αactivity qualitatively intact. Thus, the substituent may alter thedegree of inhibition of p38-α. However, as long as the compound offormula (1) retains the ability to inhibit p38-α activity, thesubstituent will be classified as “noninterfering.” A number of assaysfor determining the ability of any compound to inhibit p38-α activityare available in the art. A whole blood assay for this evaluation isillustrated below. The gene for p38-α has been cloned and the proteincan be prepared recombinantly and its activity assessed, including anassessment of the ability of an arbitrarily chosen compound to interferewith this activity. The essential features of the molecule are tightlydefined. The positions which are occupied by “noninterferingsubstituents” can be substituted by conventional organic moieties as isunderstood in the art. It is irrelevant to the present invention to testthe outer limits of such substitutions. The essential features of thecompounds are those set forth with particularity herein.

[0036] In addition, L¹ and L² are described herein as linkers. Thenature of such linkers is less important than the distance they impartbetween the portions of the molecule. Typical linkers include alkylene,i.e. (CH₂)_(n)—R; alkenylene—i.e., an alkylene moiety which contains adouble bond, including a double bond at one terminus. Other suitablelinkers include, for example, substituted alkylenes or alkenylenes,carbonyl moieties, and the like.

[0037] As used herein, “hydrocarbyl residue” refers to a residue whichcontains only carbon and hydrogen. The residue may be aliphatic oraromatic, straight-chain, cyclic, branched, saturated or unsaturated.The hydrocarbyl residue, when so stated however, may contain heteroatomsover and above the carbon and hydrogen members of the substituentresidue. Thus, when specifically noted as containing such heteroatoms,the hydrocarbyl residue may also contain carbonyl groups, amino groups,hydroxyl groups and the like, or contain heteroatoms within the“backbone” of the hydrocarbyl residue.

[0038] As used herein, “inorganic residue” refers to a residue that doesnot contain carbon. Examples include, but are not limited to, halo,hydroxy, NO₂, or NH₂.

[0039] As used herein, the term “alkyl,” “alkenyl” and “alkynyl” includestraight- and branched-chain and cyclic monovalent substituents.Examples include methyl, ethyl, isobutyl, cyclohexyl, cyclopentylethyl,2-propenyl, 3-butynyl, and the like. Typically, the alkyl, alkenyl andalkynyl substituents contain 1-10C (alkyl) or 2-10C (alkenyl oralkynyl). Preferably they contain 1-6C (alkyl) or 2-6C (alkenyl oralkynyl). Heteroalkyl, heteroalkenyl and heteroalkynyl are similarlydefined but may contain 1-2 O, S or N heteroatoms or combinationsthereof within the backbone residue.

[0040] As used herein, “acyl” encompasses the definitions of alkyl,alkenyl, alkynyl and the related hetero-forms which are coupled to anadditional residue through a carbonyl group.

[0041] The term “Aromatic” with respect to moiety Ar¹ refers to amonocyclic or fused bicyclic moiety such as phenyl or naphthyl;“heteroaromatic” also refers to monocyclic or fused bicyclic ringsystems containing one or more heteroatoms selected from O, S and N. Theinclusion of a heteroatom permits inclusion of 5-membered rings as wellas 6-membered rings. Thus, typical aromatic systems include pyridyl,pyrimidyl, indolyl, benzimidazolyl, benzotriazolyl, isoquinolyl,quinolyl, benzothiazolyl, benzofuranyl, thienyl, furyl, pyrrolyl,thiazolyl, oxazolyl, imidazolyl and the like. Any monocyclic or fusedring bicyclic system which has the characteristics of aromaticity interms of electron distribution throughout the ring system is included inthis definition. Typically, the ring systems contain 5-12 ring memberatoms.

[0042] Similarly, “arylalkyl” and “heteroalkyl” refer to aromatic andheteroaromatic systems which are coupled to another residue through acarbon chain, including substituted or unsubstituted, saturated orunsaturated, carbon chains, typically of 1-6C. These carbon chains mayalso include a carbonyl group, thus making them able to providesubstituents as an acyl moiety.

[0043] When the compounds of Formula (1) contain one or more chiralcenters, the invention includes optically pure forms as well as mixturesof stereoisomers or enantiomers

[0044] With respect to the portion of the compound between the Ar¹ andAr², linkers L² and L¹, in combination with the piperadine/piperazinering, provide for separation of the atom of Ar¹ bonded to L² from theatom of Ar² bonded to L¹ by a defined minimum number of covalent bondlengths counted end-to-end through the compound, as opposed to ameasurement of linear distance through space. More particularly, thesmallest number of bonds counted end-to-end in the compound separatingthe atom of Ar¹ bonded to L² from the atom of Ar² bonded to L¹ is atleast 5, and preferably from 6 to 12, wherein the length of each of suchbonds is 1.2 to 2.0 angstroms. In terms of a linear distance throughspace, the linear distance measured through space from the atom of Ar¹bonded to L² to the atom of Ar² bonded to L¹ is a distance of 4.5-24 Å,preferably 6-20 Å, and more preferably 7.5-10 Å.

[0045] Typical, but nonlimiting, embodiments of L¹ and L² are CO andisosteres thereof, or optionally substituted isosteres, or longer chainforms. L², in particular, may be alkylene or alkenylene optionallysubstituted with noninterfering substituents or L¹ or L² may be or mayinclude a heteroatom such as N, S or O. Such substituents include, butare limited to, a moiety selected from the group consisting of alkyl,alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl,heteroalkenyl, heteroalkynyl, heteroalkylaryl, NH-aroyl, halo, OR, NR₂,SR, SOR, SO₂R, OCOR, NRCOR, NRCONR₂, NRCOOR, OCONR₂, RCO, COOR,alkyl-OOR, SO₃R, CONR₂, SO₂NR₂, NRSO₂NR₂, CN, CF₃, R₃Si, and NO₂,wherein each R is independently H, alkyl, alkenyl or aryl or heteroformsthereof, and wherein two substituents on L² can be joined to form anon-aromatic saturated or unsaturated ring that includes 0-3 heteroatomswhich are O, S and/or N and which contains 3 to 8 members or said twosubstituents can be joined to form a carbonyl moiety or an oxime,oximeether, oximeester or ketal of said carbonyl moiety.

[0046] Isosteres of CO and CH₂, include SO, SO₂, or CHOH, CO and CH₂ arepreferred. Thus, L² is substituted with 0-2 substituents. Whereappropriate, two optional substituents on L² can be joined to form anon-aromatic saturated or unsaturated hydrocarbyl ring that includes 0-3heteroatoms such as O, S and/or N and which contains 3 to 8 members. Twooptional substituents on L² can be joined to form a carbonyl moietywhich can be subsequently converted to an oxime, an oximeether, anoximeester, or a ketal.

[0047] Ar¹ is aryl, heteroaryl, including 6-5 fused heteroaryl,cycloaliphatic or cycloheteroaliphatic that can be optionallysubstituted. Ar is preferably optionally substituted phenyl.

[0048] Each substituent on Ar¹ is independently a hydrocarbyl residue(1-20C) containing 0-5 heteroatoms selected from O, S and N, or is aninorganic residue. Preferred substituents include those selected fromthe group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl,aroyl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl,heteroalkylaryl, NH-aroyl, halo, OR, NR₂, SR, SOR, SO₂R, OCOR, NRCOR,NRCONR₂, NRCOOR, OCONR₂, RCO, COOR, alkyl-OOR, SO₃R, CONR₂, SO₂NR₂,NRSO₂NR₂, CN, CF₃, R₃Si, and NO₂, wherein each R is independently H,alkyl, alkenyl or aryl or heteroforms thereof, and wherein two of saidoptional substituents on adjacent positions can be joined to form afused, optionally substituted aromatic or nonaromatic, saturated orunsaturated ring which contains 3-8 members. More preferred substituentsinclude halo, alkyl (1-4C) and more preferably, fluoro, chloro andmethyl. These substituents may occupy all available positions of thearyl ring of Ar¹, preferably 1-2 positions, most preferably oneposition. These substituents may be optionally substituted withsubstituents similar to those listed. Of course some substituents, suchas halo, are not further substituted, as known to one skilled in theart.

[0049] Two substituents on Ar¹ can be joined to form a fused, optionallysubstituted aromatic or nonaromatic, saturated or unsaturated ring whichcontains 3-8 members.

[0050] Between L¹ and L² is a piperidine-type moiety of the followingformula:

[0051] wherein Z¹ is CR² or N and R² is H or a noninterferingsubstituent. Each of n and p is an integer from 0-2 wherein the sum of nand p is 0-3. The noninterfering substituents R² include, withoutlimitation, halo, alkyl, alkoxy, aryl, arylalkyl, aryloxy, heteroaryl,acyl, carboxy, or hydroxy. Preferably, R² is H, alkyl, OR, NR₂, SR orhalo, where R is H or alkyl. Additionally, R² can be joined with an R¹substituent to form an optionally substituted non-aromatic saturated orunsaturated hydrocarbyl ring which contains 3-8 members and 0-3heteroatoms such as O, N and/or S. Preferred embodiments includecompounds wherein Z¹ is CH or N, and those wherein both n and p are 1.

[0052] R¹ represents a noninterfering substituent such as a hydrocarbylresidue (1-20C) containing 0-5 heteroatoms selected from O, S and N.Preferably R¹ is alkyl, alkoxy, aryl, arylalkyl, aryloxy, heteroalkyl,heteroaryl, heteroarylalkyl, RCO, ═O, acyl, halo, CN, OR, NRCOR, NR,wherein R is H, alkyl (preferably 1-4C), aryl, or hetero forms thereof.Each appropriate substituent is itself unsubstituted or substituted with1-3 substituents. The substituents are preferably independently selectedfrom a group that includes alkyl, alkenyl, alkynyl, aryl, arylalkyl,acyl, aroyl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl,heteroalkylaryl, NH-aroyl, halo, OR, NR₂, SR, SOR, SO₂R, OCOR, NRCOR,NRCONR₂, NRCOOR, OCONR₂, RCO, COOR, alkyl-OOR, SO₃R, CONR₂, SO₂NR₂,NRSO₂NR₂, CN, CF₃, R₃Si, and NO₂, wherein each R is independently H,alkyl, alkenyl or aryl or heteroforms thereof and two of R¹ on adjacentpositions can be joined to form a fused, optionally substituted aromaticor nonaromatic, saturated or unsaturated ring which contains 3-8members, or R¹ is ═O or an oxime, oximeether, oximeester or ketalthereof. R¹ may occur m times on the ring; m is an integer of 0-4.Preferred embodiments of R¹ comprise alkyl (1-4C) especially two alkylsubstituents and carbonyl. Most preferably R¹ comprises two methylgroups at positions 2 and 5 or 3 and 6 of a piperidinyl or piperazinylring or ═O preferably at the 5-position of the ring. The substitutedforms may be chiral and an isolated enantiomer may be preferred.

[0053] Z is —W_(i)—COX_(j)Y wherein Y is COR³ or an isostere thereof andR³ is a noninterfering substituent. Each of W and X is a spacer and maybe, for example, optionally substituted alkyl, alkenyl, or alkynyl, eachof i and j is 0 or 1. Preferably, W and X are unsubstituted. Preferably,j is 0 so that the two carbonyl groups are adjacent to each other.Preferably, also, i is 0 so that the proximal CO is adjacent the ring.However, compounds wherein the proximal CO is spaced from the ring canreadily be prepared by selective reduction of an initially glyoxalsubstituted Ar².

[0054] The noninterfering substituent represented by R³, when R³ isother than H, is a hydrocarbyl residue (1-20C) containing 0-5heteroatoms selected from O, S and/or N or is an inorganic residue.Preferred are embodiments wherein R³ is H, or is straight or branchedchain alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroalkyl, heteroaryl,or heteroarylalkyl, each optionally substituted with halo, alkyl,heteroalkyl, SR, OR, NR₂, OCOR, NRCOR, NRCONR₂, NRSO₂R, NRSO₂NR₂,OCONR₂, CN, COOR, CONR₂, COR, or R₃Si wherein each R is independently H,alkyl, alkenyl or aryl or the heteroatom-containing forms thereof, orwherein R³ is OR, NR₂, SR, NRCONR₂, OCONR₂, or NRSO₂NR₂, wherein each Ris independently H, alkyl, alkenyl or aryl or the heteroatom-containingforms thereof, and wherein two R attached to the same atom may form a3-8 member ring and wherein said ring may further be substituted byalkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl, each optionally substituted with halo, SR, OR, NR₂,OCOR, NRCOR, NRCONR₂, NRSO₂R, NRSO₂NR₂, OCONR₂, or R₃Si wherein each Ris independently H, alkyl, alkenyl or aryl or the heteroatom-containingforms thereof wherein two R attached to the same atom may form a 3-8member ring, optionally substituted as above defined.

[0055] Other preferred embodiments of R³ are H, heteroarylalkyl, —NR₂,heteroaryl, —COOR, —NHRNR₂, heteroaryl-COOR, heteroaryloxy, —OR,heteroaryl-NR₂, —NROR and alkyl. Most preferably R³ is isopropylpiperazinyl, methyl piperazinyl, dimethylamine, piperazinyl, isobutylcarboxylate, oxycarbonylethyl, morpholinyl, aminoethyldimethylamnine,isobutyl carboxylate piperazinyl, oxypiperazinyl, ethylcarboxylatepiperazinyl, methoxy, ethoxy, hydroxy, methyl, arnine, aminoethylpyrrolidinyl, aminopropanediol, piperidinyl, pyrrolidinyl-piperidinyl,or methyl piperidinyl.

[0056] Isosteres of COR³ as represented by Y are defined as follows. Theisosteres have varying lipophilicity and may contribute to enhancedmetabolic stability. Thus, Y, as shown, may be replaced by the isosteresin Table 1.

TABLE 1 Acid Isosteres Names of Groups Chemical Structures SubstitutionGroups (SG) tetrazole

n/a 1,2,3-triazole

H; SCH₃; COCH₃; Br; SOCH₃; SO₂CH₃; NO₂; CF₃; CN; COOMe 1,2,4-triazole

H; SCH₃; COCH₃; Br; SOCH₃; SO₂CH₃; NO₂ imidazole

H; SCH₃; COCH₃; Br; SOCH₃; SO₂CH₃; NO₂

[0057] Thus, isosteres include tetrazole, 1,2,3-triazole, 1,2,4-triazoleand imidazole.

[0058] The compounds of formula (1) may be supplied in the form of theirpharmaceutically acceptable acid-addition salts including salts ofinorganic acids such as hydrochloric, sulfuric, hydrobromic, orphosphoric acid or salts of organic acids such as acetic, tartaric,succinic, benzoic, salicylic, and the like. If a carboxyl moiety ispresent on the compound of formula (1), the compound may also besupplied as a salt with a pharmaceutically acceptable cation.

Synthesis of the Invention Compounds

[0059] Copending, commonly-assigned U.S. Ser. No. 09/575,060,incorporated herein by reference in its entirety, illustrated thefollowing reaction scheme for conversion of a 4-benzylpiperidinyl-indole-5-carboxamide to the glyoxalic acid compounds of theinvention and derivatives thereof:

[0060] In the present invention, the indole moiety is generalized to Ar²in formula (1) above where Ar² is a substantially planar, monocyclic orpolycyclic aromatic moiety having one or more optional ring heteroatoms,said moiety being optionally substituted with one or morenon-interfering substituents, two or more of which may form a fuisedring. Preferably the moiety Ar² comprises an optionally substitutedmonocyclic or polycyclic aromatic nucleus, wherein said aromatic nucleusconsists of carbocyclic or heterocyclic ring selected from (i) afive-membered heterocyclic or carbocyclic ring (ii) a six-memberedcarbocyclic or heterocyclic ring; (iii) a five-membered carbocyclic orheterocycloc ring fused to another five-membered carbocyclic orheterocyclic ring; (iv) a six-membered carbocyclic or heterocyclic ringfused to another six-membered carbocyclic or heterocyclic ring; and (v)a five-membered heterocyclic or carbocyclic ring fused to a six-memberedcarbocyclic or heterocyclic ring. Formula (1), as required by theproviso stated above, excludes the indole type compounds disclosed andclaimed in U.S. Ser. No. 09/575,060 filed May 21, 1999 and incorporatedherein by reference.

[0061] As disclosed commonly assigned in U.S. Ser. No. 09/575,060, theglyoxal type substituent at position 3 can be generalized to—W_(i)COX_(j)Y.

[0062] The Ar² moiety may be generalized as:

[0063] Methods to synthesize the compounds of the invention are, ingeneral, known in the art. For example, commonly assigned U.S. Ser. No.09/575,060, incorporated herein by reference in its entirety, disclosedthat piperidine moieties can be obtained using the following reactionscheme

[0064] where an appropriate piperidone such as I, is treated withsubstituted benzyl phosphonate esters in the presence of a base such assodium hydride to give alkenes which can be reduced to the correspondingsubstituted 4-benzylpiperidine such as II. The hydrogenations aretypically done in the presence of catalytic metals in solvents such asmethanol, ethanol and ethyl acetate.

[0065] An alternative to the above disclosed in U.S. Ser. No. 09/575,060as follows:

[0066] where isonipecotoyl chlorides such as I can be used to acylateappropriately substituted benzenes (ArH) in the presence of a Lewis acidsuch as aluminum chloride to give the ketones II. Further modificationsof the carbonyl moiety of II using methods and routes generally knowncan then lead to the desired compounds III.

[0067] The following reaction schemes illustrate methods for preparingcompounds of the present invention.

[0068] Assays for p38 α Kinase Inhibition

[0069] For each of the assay procedures described below, the TNF-αproduction correlates to the activity of p38-α kinase.

[0070] A. Human Whole Blood Assay for p38 Kinase Inhibition

[0071] Venous blood is collected from healthy male volunteers into aheparinized syringe and is used within 2 hours of collection. Testcompounds are dissolved in 100% DMSO and 1 μl aliquots of drugconcentrations ranging from 0 to 1 mM are dispensed into quadruplicatewells of a 24-well microtiter plate (Nunclon Delta SI, AppliedScientific, So. San Francisco, Calif.). Whole blood is added at a volumeof 1 ml/well and the mixture is incubated for 15 minutes with constantshaking (Titer Plate Shaker, Lab-Line Instruments, Inc., Melrose Park,Ill.) at a humidified atmosphere of 5% CO₂ at 37° C. Whole blood iscultured either undiluted or at a final dilution of 1:10 with RPMI 1640(Gibco 31800 +NaHCO₃, Life Technologies, Rockville, Md. and Scios, Inc.,Sunnyvale, Calif.). At the end of the incubation period, 10 μl of LPS(E. coli 0111:B4, Sigma Chemical Co., St. Louis, Mo.) is added to eachwell to a final concentration of 1 or 0.1 μg/ml for undiluted or 1:10diluted whole blood, respectively. The incubation is continued for anadditional 2 hours. The reaction is stopped by placing the microtiterplates in an ice bath and plasma or cell-free supemates are collected bycentrifugation at 3000 rpm for 10 minutes at 4° C. The plasma samplesare stored at −80° C. until assayed for TNF-α levels by ELISA, followingthe directions supplied by Quantikine Human TNF-α assay kit (R&DSystems, Minneapolis, Minn.).

[0072] IC₅₀ values are calculated using the concentration of inhibitorthat causes a 50% decrease as compared to a control.

[0073] B. Enriched Mononuclear Cell Assay for p38 Kinase Inhibition

[0074] The enriched mononuclear cell assay, the protocol of which is setforth below, begins with cryopreserved Human Peripheral BloodMononuclear Cells (HPBMCs) (Clonetics Corp.) that are rinsed andresuspended in a warm mixture of cell growth media. The resuspendedcells are then counted and seeded at 1×10⁶ cells/well in a 24-wellmicrotitre plate. The plates are then placed in an incubator for an hourto allow the cells to settle in each well.

[0075] After the cells have settled, the media is aspirated and newmedia containing 100 ng/ml of the cytokine stimulatory factorLipopolysaccharide (LPS) and a test chemical compound is added to eachwell of the microtiter plate. Thus, each well contains HPBMCs, LPS and atest chemical compound. The cells are then incubated for 2 hours, andthe amount of the cytokine Tumor Necrosis Factor Alpha (TNF-α) ismeasured using an Enzyme Linked Inmunoassay (ELISA). One such ELISA fordetecting the levels of TNF-α is commercially available from R&DSystems. The amount of TNF-α production by the HPBMCs in each well isthen compared to a control well to determine whether the chemicalcompound acts as an inhibitor of cytokine production.

[0076] LPS Induced Cytokine Synthesis in HPBMCs

[0077] Cryopreserved HPBMC (cat #CC-2702 Clonetics Corp)

[0078] LGM-3 media (cat #CC-3212 Clonetics Corp)

[0079] LPS stock 10 μg/ml (Cat. No. L 2630 serotype 0111:B4 Sigma)

[0080] Human TNF-α ELISA (R&D Systems)

[0081] DNase I (10 mg/ml stock)

[0082] Preparation of Cells

[0083] LGM-3 media warmed to 37° C.

[0084] 5 μl of DNase I stock added to 10 ml media.

[0085] Cells thawed rapidly and dispersed into above.

[0086] Centrifuge 200×g×10 min @ RT.

[0087] Pellet up in 10 ml sterile PBS.

[0088] Centrifuge 200×g×10 min @ RT.

[0089] Pellet resuspended in 10 ml LGM-3 then diluted to 50 ml withLGM-3.

[0090] Perform cell count.

[0091] Adjust to 1×E06 cells/well.

[0092] Seed 1 ml/well of a 24 well plate.

[0093] Place plate in incubator to plate down for 1 hour.

[0094] Preparation of Incubation Media

[0095] LGM-3 containing 100 ng/ml LPS (e.g. 50 ml media plus 0.5 ml LPSstock) Aliquot into 2 ml aliquots and add 1000×inhibitor dilutions.

[0096] Incubation

[0097] When cells have plated down aspirate media away and overlay with1 ml relevant incubation media. Return plate to incubator for 2 hours or24 hours. Remove supernatants after incubation to a labeled tube andeither perform TNF (or other) ELISA immediately or freeze for laterassay.

[0098] IC₅₀ values are calculated using the concentration of inhibitorthat causes a 50% decrease as compared to a control.

[0099] Administration and Use

[0100] The compounds of the invention are useful among other indicationsin treating conditions associated with inflammation. Thus, the compoundsof formula (1) or their pharmaceutically acceptable salts are used inthe manufacture of a medicament for prophylactic or therapeutictreatment of mammals, including humans, in respect of conditionscharacterized by excessive production of cytokines and/or inappropriateor unregulated cytokine activity on such cells as cardiomyocytes,cardiofibroblasts and macrophages.

[0101] The compounds of the invention inhibit the production ofcytokines such as TNF, IL-1, IL-6 and IL-8, cytokines that are importantproinflammatory constituents in many different disease states andsyndromes. Thus, inhibition of these cytokines has benefit incontrolling and mitigating many diseases. The compounds of the inventionare shown herein to inhibit a member of the MAP kinase family variouslycalled p38 MAPK (or p38), CSBP, or SAPK-2. The activation of thisprotein has been shown to accompany exacerbation of the diseases inresponse to stress caused, for example, by treatment withlipopolysaccharides or cytokines such as TNF and IL-1. Inhibition of p38activity, therefore, is predictive of the ability of a medicament toprovide a beneficial effect in treating diseases such as Alzheimer's,coronary artery disease, congestive heart failure, cardiomyopathy,myocarditis, vasculitis, restenosis, such as occurs following coronaryangioplasty, atherosclerosis, IBD, rheumatoid arthritis, rheumatoidspondylitis, osteoarthritis, gouty arthritis and other arthriticconditions, multiple sclerosis, acute respiratory distress syndrome(ARDS), asthma, chronic obstructive pulmonary disease (COPD), silicosis,pulmonary sarcosis, sepsis, septic shock, endotoxic shock, Gram-negativesepsis, toxic shock syndrome, heart and brain failure (stroke) that arecharacterized by ischemia and reperfusion injury, surgical procedures,such as transplantation procedures and graft rejections, cardiopulmonarybypass, coronary artery bypass graft, CNS injuries, including open andclosed head trauma, inflammatory eye conditions such as conjunctivitisand uveitis, acute renal failure, glomerulonephritis, inflammatory boweldiseases, such as Crohn's disease or ulcerative colitis, graft vs. hostdisease, bone resorption diseases like osteoporosis, type II diabetes,pyresis, psoriasis, cachexia, viral diseases such as those caused byHIV, CMV, and Herpes, and cerebral malaria.

[0102] Within the last several years, p38 has been shown to comprise agroup of MAP kinases designated p³⁸-α, p38-β, p38-65 and p38-δ. Jiang,Y., et al., J. Biol Chem (1996) 271:17920-17926 reportedcharacterization of p38-β as a 372-amino acid protein closely related top38-α. In comparing the activity of p38-α with that of p38-β, theauthors state that while both are activated by proinflammatory cytokinesand environmental stress, p38-β was preferentially activated by MAPkinase kinase-6 (MKK6) and preferentially activated transcription factor2, thus suggesting that separate mechanisms for action may be associatedwith these forms.

[0103] Kumar, S., et al., Biochem Biophys Res Comm (1997) 235:533-538and Stein, B., et al., J Biol Chem (1997) 272:19509-19517 reported asecond isoform of p38-β, p38-β2, containing 364 amino acids with 73%identity to p38-α. All of these reports show evidence that p38-β isactivated by proinflammatory cytokines and environmental stress,although the second reported p38-β isoform, p38-β2, appears to bepreferentially expressed in the CNS, heart and skeletal muscle comparedto the more ubiquitous tissue expression of p38-α. Furthermore,activated transcription factor-2 (ATF-2) was observed to be a bettersubstrate for p38-β2 than for p38-α, thus suggesting that separatemechanisms of action may be associated with these forms. Thephysiological role of p38-β1 has been called into question by the lattertwo reports since it cannot be found in human tissue and does notexhibit appreciable kinase activity with the substrates of p38-α.

[0104] The identification of p38-γ was reported by Li, Z., et al.,Biochem Biophys Res Comm (1996) 228:334-340 and of p38-δ by Wang, X., etal., J Biol Chem (1997) 272:23668-23674 and by Kumar, S., et al.,Biochem Biophys Res Comm (1997) 235:533-538. The data suggest that thesetwo p38 isoforms (γ and δ) represent a unique subset of the MAPK familybased on their tissue expression patterns, substrate utilization,response to direct and indirect stimuli, and susceptibility to kinaseinhibitors.

[0105] Various results with regard to response to drugs targeting thep38 family as between p38-α and either the putative p38-β1 or p38-β2 orboth were reported by Jiang, Kumar, and Stein cited above as well as byEyers, P. A., et al., Chem and Biol (1995) 5:321-328. An additionalpaper by Wang, Y., et al., J Biol Chem (1998) 273:2161-2168 suggests thesignificance of such differential effects. As pointed out by Wang, anumber of stimuli, such as myocardial infarction, hypertension, valvulardiseases, viral myocarditis, and dilated cardiomyopathy lead to anincrease in cardiac workload and elevated mechanical stress oncardiomyocytes. These are said to lead to an adaptive hypertrophicresponse which, if not controlled, has decidedly negative consequences.Wang cites previous studies which have shown that in ischemiareperfusion treated hearts, p38 MAPK activities are elevated inassociation with hypertrophy and programmed cell death. Wang shows inthe cited paper that activation of p38-β activity results inhypertrophy, whereas activation of p38-α activity leads to myocyteapoptosis. Thus, selective inhibition of p38-α activity as compared top38-β activity will be of benefit in treating conditions associated withcardiac failure. These conditions include congestive heart failure,cardiomyopathy, myocarditis, vasculitis, vascular restenosis, valvulardisease, conditions associated with cardiopulmonary bypass, coronaryartery bypass, grafts and vascular grafts. Further, to the extent thatthe α-isoform is toxic in other muscle cell types, α-selectiveinhibitors would be useful for conditions associated with cachexiaattributed to TNF or other conditions such as cancer, infection, orautoimmune disease.

[0106] Thus, the invention encompasses the use of compounds whichselectively inhibit the activity of the p38-α isoform for treatingconditions associated with activation of p³⁸-α, in particular thoseassociated with cardiac hypertrophy, ischemia or other environmentalstress such as oxidation injury, hyperosmolarity or other agents orfactors that activate p38-α kinase, or cardiac failure, for example,congestive heart failure, cardiomyopathy and myocarditis.

[0107] The manner of administration and formulation of the compoundsuseful in the invention and their related compounds will depend on thenature of the condition, the severity of the condition, the particularsubject to be treated, and the judgement of the practitioner;formulation will depend on mode of administration. As the compounds ofthe invention are small molecules, they are conveniently administered byoral administration by compounding them with suitable pharmaceuticalexcipients so as to provide tablets, capsules, syrups, and the like.Suitable formulations for oral administration may also include minorcomponents such as buffers, flavoring agents and the like. Typically,the amount of active ingredient in the formulations will be in the rangeof 5%-95% of the total formulation, but wide variation is permitteddepending on the carrier. Suitable carriers include sucrose, pectin,magnesium stearate, lactose, peanut oil, olive oil, water, and the like.

[0108] The compounds useful in the invention may also be administeredthrough suppositories or other transmucosal vehicles. Typically, suchformulations will include excipients that facilitate the passage of thecompound through the mucosa such as pharmaceutically acceptabledetergents.

[0109] The compounds may also be administered topically, for topicalconditions such as psoriasis, or in formulation intended to penetratethe skin. These include lotions, creams, ointments and the like whichcan be formulated by known methods. The compounds may also beadministered by injection, including intravenous, intramuscular,subcutaneous or intraperitoneal injection. Typical formulations for suchuse are liquid formulations in isotonic vehicles such as Hank's solutionor Ringer's solution.

[0110] Alternative formulations include nasal sprays, liposomalformulations, slow-release formulations, and the like, as are known inthe art.

[0111] Any suitable formulation may be used. A compendium of art-knownformulations is found in Remington's Pharmaceutical Sciences, latestedition, Mack Publishing Company, Easton, Pa. Reference to this manualis routine in the art.

[0112] The dosages of the compounds of the invention will depend on anumber of factors which will vary from patient to patient. However, itis believed that generally, the daily oral dosage will utilize 0.001-100mg/kg total body weight, preferably from 0.01-50 mg/kg and morepreferably about 0.01 mg/kg-10 mg/kg. The dose regimen will vary,however, depending on the conditions being treated and the judgment ofthe practitioner.

[0113] It should be noted that the compounds of formula (1) can beadministered as individual active ingredients, or as mixtures of severalembodiments of this formula. In addition, the inhibitors of p38 kinasecan be used as single therapeutic agents or in combination with othertherapeutic agents. Drugs that could be usefully combined with thesecompounds include natural or synthetic corticosteroids, particularlyprednisone and its derivatives, monoclonal antibodies targeting cells ofthe immune system, antibodies or soluble receptors or receptor fusionproteins targeting immune or non-immune cytokines, and small moleculeinhibitors of cell division, protein synthesis, or MRNA transcription ortranslation, or inhibitors of immune cell differentiation or activation.

[0114] As implied above, although the compounds of the invention may beused in humans, they are also available for veterinary use in treatinganimal subjects.

[0115] The following examples are intended to illustrate but not tolimit the invention. The compounds described and prepared in examples1-4 below are inhibitors of p38-α kinase.

EXAMPLE 1{3-[4-(4-Fluoro-benzyl)-piperidine-1-carbonyl]-4-methoxy-phenyl}-oxo-aceticacid methyl ester

[0116]

[0117] Under nitrogen protection, to a 250 mL R.B. dry flask containing5.6 g (24.4 mMol) 4-fluoro-benzyl piperidine HCl salt was added 100 mlanhydrous CH₂Cl₂, followed by addition of 3.48 ml triethylamine (25mMol). The suspension was allowed to stir at room temperature for a fewminutes until it became a clear solution. To this solution was thenadded 4.37 g 5-formylsalicyclic acid (25 mMol ), 4.8 g (25 mMol ) of1-ethyl-3-(3-dimethyl aminopropyl)-carbodiimide, 0.153 g (1.25 mMol ) of4-(dimethylamino)-pyridine. After overnight stirring, the reactionmixture was diluted with 100 mL of CH₂Cl₂, washed with H₂O, brine. Theorganic layers were then dried over anhydrous sodium sulfate,concentrated and purified by column chromatography eluting with CH₂Cl₂,giving 3.65 g (10.7 mMol ) of desired product. (yield: 43.8%)

[0118] 3.62 gram (10.6 mMol ) aldehyde was dissolved in 100 mL anhydrousDMF under an argon atmosphere. To this solution, at 0° C. was added 4.66g NaH (60% dispersion in mineral oil, 11.7 mMol). The reaction wasallowed to stir at 0° C. for 0.5 h before warming up to roomtemperature, stirring continued until there were no more bubblesproduced. The flask was then cooled to 0° C. again, followed by additionof 0.73 mL of methyl iodide (11.7 mMol). After stirring at 0° C. for 0.5h, the reaction was warmed up to room temperature, and continuedstirring for another 4 h. DMF was evaporated off under reduced pressure.The resulting residue was re-dissolved in 100 mL of CH₂Cl₂, washed twicewith H₂O, and brine. Organic layers were dried over anhydrous sodiumsulfate, concentrated and purified by column chromatography in agradient of 100% CH₂Cl₂ to 2% MeOH/CH₂Cl₂. 2.65 g (7.46 mMol) of productwas obtained in a yield of 70.4%.

[0119] Under nitrogen protection, 2.64 g (7.43 mMol ) of aldehyde wasdissolved in 75 mL anhydrous THF. At 0° C., to this solution was added1.1 mL of trimethylsilyl cyanide (8.2 mMol ), followed by addition of2-3 drops of n-butyllithium (2.5 M solution in hexane). Stirring at 0°C. was continued for 2 h before warmed up to room temperature andstirred overnight. After removing solvents by rotary evaporation,product was obtained in almost quantitative yield as a white power.Without further purification, the material was used directly in nextstep.

[0120] The material obtained from last step was diluted with 60 mL ofconcentrated HCl and heated to 80° C. with an oil bath overnight. Afterovernight heating, the aqueous solution was diluted with 100 mL H₂O andaqueous solution was extracted with CH₂Cl₂ (100 mL×3). Organic layerswere washed with brine, dried over sodium sulfate, and concentrated. Theresidue was then re-dissolved in about 70 mL MeOH, followed by additionof 1.7 g (30.3 mMol) of KOH and the solution was warmed to reflux for 2h. Reaction was then cooled to room temperature, concentrated, and driedunder vacuum. Several grams of crushed ice was added into the flask andacidified with 10% aqueous HCl. Water (60 mL) was added to dilute thesolution, and this aqueous solution was extracted with CH₂Cl₂ (100mL×3). Organic layers were washed with brine, dried over sodium sulfate,concentrated to give 2.5 g (6.23 mMol) of product.

[0121] In a 50 mL R.B. flask containing a condenser, 130 mg of α-hydroxyacid was dissolved in 4 ml of concentrated HCl:MeOH (1:9) and warmed toreflux. After 1 h, the reaction was cooled to RT and concentrated underreduced pressure. Resulting residue was re-dissolved in 20 mL ethylacetate and the ethyl acetate layer was washed with 20 mL H₂O, twicewith 20 ml saturated NaHCO₃ solution, and brine. Organic layer was driedover anhydrous sodium sulfate and concentrated to give 141 mg of crudeproduct.

[0122] 123 mg of methyl ester was dissolved in 4 ml CH₂Cl₂ followed byaddition of excess of pyridinium chloromate (1 g, 20 wt. % on basicalumina). The resulting suspension was stirred at room temperature over24 hours. Solid was filtered and washed with CH₂Cl₂. Combined organicsolution was concentrated and product was purified by Preparativethin-layer chromatography with 1% MeOH/CH₂Cl₂ as eluting solution, togive 26 mg of desired product.

EXAMPLE 22-{2-[4-(4-Fluoro-benzyly)-piperidine-1-carbonyl]-3-methyl-imidazo[2,1-b]thiazol-5-yl}-N,N-dimethyl-2-oxo-acetamide

[0123]

[0124] Thiourea (3.81 g) and ethyl 2-chloroacetoacetate (8.23 g)werecombined in EtOH (100 mL) and heated at reflux for 14 h. After coolingto RT the EtOH was removed in vacuo and the crude product dissolved inH₂O and neutralized with NaHCO₃ followed by extraction with ethylacetate. The combined extracts were dried, filtered, and concentrated toyield the product as a white powder (8.69 g).

[0125] To bromoacetaldehyde diethylacetal (11.2 mMol, 2.20 g) in H₂O (75mL) was added concentrated HCl (1.15 mL) dropwise. After stirring at RTfor 14 h the mixture was heated at 80° C. for 30 min. After cooling toRT NaHCO₃ (14.5 mMol, 1.22 g) was cautiously added and stirring wascontinued for 2 h. The ester (8.9 mMol, 1.66 g) was then added and themix was stirred an additional 1 h before adding dioxane (50 mL). After30 min the mix was heated to 100° C. for 48 h. After cooling to RT thedioxane was removed by rotary evaporation. The aqueous layer wasextracted with CH₂Cl₂. The combined organics were dried (Na₂SO₄),filtered and concentrated. Radial chromatography (10% MeOH in CH₂Cl₂)yielded 122 mg of the desired product.

[0126] To the ester (0.19 mMol, 40 mg) in toluene (0.76 mL) at RT wasadded a 2.0 M solution of oxalyl chloride in CH₂Cl₂ (0.285 mL). Thereaction vessel was placed under N₂, sealed, and placed at 125° C. for12 h. After cooling to RT the volatiles were removed under vacuum. Tothe crude acid chloride was added CH₂Cl₂ (0.76 mL) and after cooling to0° C. a 2.0 M solution of dimethylamine in THF (0.285 mL)was addeddropwise. The reaction mixture was stirred an additional 30 min at 0° C.and then warmed to RT. After 30 min the reaction was quenched with H₂Oand extracted with CH₂Cl₂. The combined extracts were washed with brineand then dried (Na₂SO₄), filtered and concentrated. After radialchromatography (10% MeOH in CH₂Cl₂) 38 mg of the product was obtained.

[0127] To the ester (0.12 mMol, 38 mg) in MeOH (0.25 mL) and H₂O (0.25mL) was added NaOH (0.985 N in H₂O, 122 μL). The mixture was stirred atRT for 14 h at which time it was acidified with aq. HCl and extractedwith ethyl acetate. The combined extracts were dried (Na₂SO₄), filtered,and concentrated to yield 19 mg of the product which carried on to thenext step without purification.

[0128] To the acid (0.14 mMol, 19 mg) in CH₂Cl₂ (0.56 mL) was added4-fluorobenzylpiperidine (0.17 mMol, 39 mg) followed by EDC (0.17 mMol,33 mg) and DMAP (4 mg). The mix was stirred at RT for 14 h beforequenching with H₂O and extracting with CH₂Cl₂. The combined extractswere dried (Na₂SO₄), filtered, and concentrated. After radialchromatography 20 mg of the desired compound was obtained.

EXAMPLE 32-{6-[4-(4-Fluoro-benzyl)-piperidine-1-carbonyl]-imidazo[1,2-a]pyridin-3-yl}-N,N-dimethyl-2-oxo-acetamide

[0129]

[0130] To 6-aminonicotinic acid (75 mMol, 10.36 g) in MeOH (300 mL) at−78° C. was added SOCl₂ (187.5 mMol, 22.31 g, 13.7 mL) dropwise over 30min. The mixture was then allowed to RT. The mix was then refluxed for12 h at which time it was cooled and the volatiles removed using rotaryevaporation. The resulting white solid was dissolved in H₂O, neutralizedwith NaHCO₃, and extracted with ethyl acetate. The combined organicswere dried (Na₂SO₄), filtered, and concentrated to yield 10.06 g of awhite powder.

[0131] To bromoacetaldehyde diethylacetal (44.6 mMol, 8.79 g) in H₂O(300 mL) was added concentrated HCl (4.6 mL) dropwise. After stirring atRT for 14 h the mixture was heated at 80° C. for 30 min. After coolingto RT, NaHCO₃ (58.7 mMol, 4.88 g) was cautiously added and stirring wascontinued for 2 h. The ester (35.6 mMol, 5.41 g) was then added and themix was stirred an additional 1 h before adding dioxane (200 mL). After30 min the mix was heated to 100° C. for 48 h. After cooling to RT thedioxane was removed by rotary evaporation. The aqueous layer wasextracted with CH₂Cl₂. The combined organics were dried (Na₂SO₄),filtered and concentrated to yield a yellow paste (217 mg) which wascarried on to the next step without further purification.

[0132] Synthesis of2-{6-[4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-imidazo[1,2-a]pyridin-3-yl}-N,N-dimethyl-2-oxo-acetamidewas carried out through the same series of steps as for2-{2-[4-(4-Fluoro-benzyl)-piperidine-1-carbonyl]-3-methyl-imidazo[2,1-b]thiazol-5-yl}-N,N-dimethyl-2-oxo-acetamide.

EXAMPLE 42-{4-[4-(4-Fluoro-benzyl)-2,5-trans-dimethyl-piperazine-1-carbonyl]-2.5-dimethyl-1H-pyrrol-3-yl}-N,N-dimethyl-2-oxo-acetamide

[0133]

[0134] To 2,5-Dimethyl-1H-pyrrole-3-carboxylic acid (1.09 g) and1-(4-Fluoro-benzyl)-trans-2,5-dimethyl-piperazine (1.59 g) in CH₂Cl₂ wasadded EDCI (1.51 g) and catalytic DMAP. The reaction mixture was stirredat RT for 12 h at which time it H₂O was added. The mix was extractedwith CH₂Cl₂. The combined extracts were dried, filtered, andconcentrated. After column chromatography (silica gel, (1:2) ethylacetate/hexane to (7:3) ethyl acetate/hexane) 540 mg of the desiredproduct was obtained.

[0135] A solution of(2,5-dimethyl-1H-pyrrol-3-yl)-[4-(4-fluoro-benzyl)-trans-2,5-dimethyl-piperazine-1-yl]-methanone(340 mg) in CH₂Cl₂ (25 mL)was cooled to 0° C. and a solution of oxalylchloride (2.0 M in CH₂Cl₂, 2.0 mL) was added. Stirring was continued for1 h at 0° C. and then the mix was allowed to warm to RT and stir for 1h. The solvent was removed in vacuo and then replaced with CH₂Cl₂ (25mL). After cooling to 0° C. dimethylamine (2.0 M solution in THF, 4.0mL)was added dropwise. Stirring was continued for 30 min at which timeit was warmed to RT. After 30 min the reaction was quenched with H₂O andextracted with CH₂Cl₂. The combined extracts were dried, filtered, andconcentrated to yield the desired product which was purified by silicagel column chromatography ((1:1) ethyl acetate/hexane to ethyl acetatefollowed by (95:5) ethyl acetate/methanol to (90:10) ethylacetate/methanol) to yield 60 mg of the product.

ADDITIONAL EXAMPLES

[0136]

[0137] Synthesis of D

[0138] STEP 1: The phosphonate A (38.4 g) and the piperidone B (35.4)were dissolved in anhydrous dimethylformamide (400 mL). To this sodiumhydride (60% suspension in oil) was added in portions while the reactionis maintained at 0° C. After the addition of sodium hyride was completethe reaction mixture was stirred for 30 min. and then the ice bath wasremoved, the reaction was allowed to stir for 6 h as it slowly warmed toambient temperature. The reaction was again cooled in an ice bath andquenched with methanol. Water was added to the reaction mixture, and theproduct extracted with ethyl acetate. The ethyl acetate layer was washedwith saturated sodium chloride and dried over anhydrous magnesiumsulfate. The solvent was removed to gives the crude alkene, which ispurified by column chromatography eluting with ethyl acetate/hexane(1:9) to give 21.8 g of the desired product C.

[0139] STEP 2: 10.1 g of C was dissolved in 50 mL methanol. Afterpurging the solution with nitrogen, 5% Palladium on carbon (1 g)catalyst was added followed by 1 mL acetic acid. The parr containercontaining the reaction mixture was hydrogenated for 4 h at 40-50 psi.The reaction mixture was filtered through celite and concentrated. Theresidue was treated with 2 M hydrochloric acid in ether to convert tothe hydrochloric acid salt. The white solid that was obtained was driedunder vacuum, extensively, to give 7.8 g of D as the hydrochloric acidsalt.

[0140] Synthesis of II

[0141] STEP 1: To a solution of dimethyl piperazine I (25 g) in 300 mlof absolute ethanol was added 400 ml of 2N hydrogen chloride in diethylether. The solution was warmed to 70° C. in an oil bath for 20 minutes.The solution was then cooled to room temperature and set at 6° C.overnight. The solid obtained, was collected by filtration. Yield 39.8 g(dihydrochloride salt of trans-2,5 dimethylpiperazine) after dryingovernight under high vacuum.

[0142] STEP 2: An ethanol solution of 42.9 g of dimethyl piperazinedihydrochloride from STEP 1 and 26.1 g trans-2,5 dimethylpiperazine wasvigorously stirred in an oil bath at 80° C. until all starting materialswere dissolved. The temperature of oil bath was reduced to 65° C. and33.1 g of 4-fluro benzylchloride was added. After stirring at thistemperature for 30 min., the solution was placed in a 6° C. refrigeratorovernight. The solid was removed from the solution by filtration andexcess of 2N hydrogen chloride in diethyl ether was added to thefiltrate. The filtrate was kept at 6° C. overnight and the solidcollected. The solid was suspended in 5% sodium hydroxide aqueoussolution and extracted three times with ethyl acetate. The organic layerwas dried over sodium sulfate and dried down to give a yellow oil.

[0143] STEP 3: A solution of 50.7 g (L)-tartaric acid in 130 ml ofboiling methanol was added to 70 ml of hot methanol solution of 37.5 gof the product from STEP 2. The solution was set at 6° C. for 96 hoursbefore collection of white fine crystals by filtration. This materialwas recrystallized from boiling methanol. The product was collected byfiltration after being kept at a 6° C. overnight. Yield 30.5 g ofditartaric acid salt ([α]=+43.2°, c=1).

1. A compound of the formula:

and the pharmaceutically acceptable salts thereof, or a pharmaceuticalcomposition thereof, wherein: Ar¹ is an aryl group substituted with 0-5non-interfering substituents, wherein two adjacent noninterferingsubstituents can form a fused aromatic or nonaromatic ring; L¹ and L²are linkers; each R¹ is independently a noninterfering substituent; Z¹is CR² or N wherein R² is hydrogen or a noninterfering substituent; m is0-4; each of n and p is an integer from 0-2 wherein the sum of n and pis 0-3; Ar² is a substantially planar, monocyclic or polycyclic aromaticmoiety having one or more optional ring heteroatoms, said moiety beingoptionally substituted with one or more non-interfering substituents,two or more of which may form a fused ring; Z is —W_(i)—COX_(j)Y whereinY is COR³ or an isostere thereof; R³ is a noninterfering substituent,each of W and X is a spacer of 2-6 Å, and each of i andj isindependently 0 or 1; wherein the smallest number of covalent bonds inthe compound separating the atom of Ar¹ bonded to L² to the atom of Ar²bonded to L¹ is at least 6, where each of said bonds has a bond lengthof 1.2 to 2.0 angstroms; and/or wherein the distance in space betweenthe atom of Ar¹ bonded to L² and the atom of Ar² bonded to L¹ is 4.5-24angstroms; with the proviso that the portion of the compound representedby Ar²—Z is not

 wherein

represents a single or double bond; n is 0-3; one Z² is CA or CRA andthe other is CR, CR₂, NR or N; A is —W_(i)—COX_(j)Y wherein Y is COR oran isostere thereof, each of W and X is a spacer of 2-6 Å, and each of iand j is independently 0 or 1; Z³ is NR or O; and each R isindependently hydrogen or a noninterfering substituent.
 2. The compoundof claim 1 wherein said smallest number of bonds is 6-12.
 3. Thecompound of claim 1 wherein Z is COX_(j)COR³, and wherein R³ is H, or isstraight or branched chain alkyl, alkenyl, alkynyl, aryl, arylalkyl,heteroalkyl, heteroaryl, or heteroarylalkyl, each optionally substitutedwith halo, alkyl, heteroalkyl, SR, SOR, SO₂R, SO₂NR₂, OR, NR₂, OCOR,NRCOR, NRCONR₂, NRSO₂R, NRSO₂NR₂, OCONR₂, CN, COOR, CONR₂, COR, or R₃Siwherein each R is independently H, alkyl, alkenyl or aryl or theheteroatom-containing forms thereof, or wherein R³ is OR, NR₂, SR,NRCONR₂, OCONR₂, or NRSO₂NR₂, wherein each R is independently H, alkyl,alkenyl or aryl or the heteroatom-containing forms thereof, and whereintwo R attached to the same atom may form a 3-8 member carbocyclic orheterocyclic ring and wherein said ring may further be substituted byalkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl, each optionally substituted with halo, SR, OR, NR₂,OCOR, NRCOR, NRCONR₂, NRSO₂R, NRSO₂NR₂, OCONR₂, or R₃Si wherein each Ris independently H, alkyl, alkenyl or aryl or the heteroatom-containingforms thereof wherein two R attached to the same atom may form a 3-8member ring, optionally substituted as above defined; and X, if present,is CR₂ where R is as defined above.
 4. The compound of claim 1 wherein Yis an isostere of COR³.
 5. The compound of claim 4 wherein Y istetrazole; 1,2,3-triazole; 1,2,4-triazole; or imidazole.
 6. The compoundof claim 1 wherein each of i and j is
 0. 7. The compound of claim 3wherein j is
 0. 8. The compound of claim 1 wherein —Ar²-comprises anoptionally substituted monocyclic or polycyclic aromatic nucleus,wherein said aromatic nucleus consists of carbocyclic or heterocyclicring selected from (i) a five-membered heterocyclic or carbocyclic ring(ii) a six-membered carbocyclic or heterocyclic ring; (iii) afive-membered carbocyclic or heterocycloc ring fused to anotherfive-membered carbocyclic or heterocyclic ring; (iv) a six-memberedcarbocyclic or heterocyclic ring fused to another six-memberedcarbocyclic or heterocyclic ring; and (v) a five-membered heterocyclicor carbocyclic ring fused to a six-membered carbocyclic or heterocyclicring.
 9. The compound of claim 8 wherein Ar² is selected from:

where R is a noninterfering substituent.
 10. The compound of claim 8wherein the portion of said compound represented by L¹—Ar²—Z is selectedfrom the following:

wherein n is 0, 1 or 2; X¹ is NR, CR₂, O or S; and each R isindependently H or a noninterfering substituent; and two or more Rgroups may form a fused ring;

wherein n is 0-4; R is H or a noninterfering substituent where two ormore R groups may form a fused ring; and one or more ring carbons may beoptionally replaced with nitrogen;

wherein each n is inpendently 0 to 3; R is H or a noninterferingsubstituent, where two or more R groups may form a fused ring; and oneor more ring carbons may be optionally replaced with nitrogen;

wherein, subject to the proviso of claim 1, one B is L¹ and the other isZ; wherein a is 0 to 4 such that the positions on the six membered rings(1) and (3) to which (R)_(a) is bonded can include X² when X² is C; b is0-3 such that the positions on the five-membered rings (2) and (4) towhich (R)_(b) is bonded can include X² and X¹, when X² is C and X¹ is Nor C; each X² is independently N or CR; X¹ is NR, CR₂, O or S; each R isH or a noninterfering substituent where two or more R groups may form afused ring; wherein one or more of the ring carbons that are atpositions other than X² or X¹ and that are also not bound to B can beoptionally replaced with N;

wherein one B is L¹ and the other is Z; a is 0-4 such that the positionson the rings (1) and (3) to which (R)_(a) can be bonded include X² andX¹ where X² is C and X¹ is C or N; b is 0 or 3 such that the positionson the rings (2) and (4) to which (R)_(b) can be bonded include X¹, X²and X³ when X¹ is C or N and X² and/or X³ are C; each X¹ isindependently NR, C(R)₂, O or S; X² and X³ are independently N or CR;each R is independently H or a noninterfering substituent where two ormore R groups can optionally form a fused ring; wherein one or more ofthe ring carbons that are at positions other than X¹, X² or X³, and thatare also not bound to B, can be optionally replaced with N.
 11. Thecompound of claim 10 wherein L¹—Ar²—Z is structure (I).
 12. The compoundof claim 11 wherein X¹ in structure (I) is NR.
 13. The compound of claim12 wherein X¹ in structure (I) is NH.
 14. The compound of claim 13wherein R is methyl.
 15. The compound of claim 14 wherein n is
 2. 16.The compound of claim 15 wherein structure (I) is:


17. The compound of claim 16 where the compound is:


10. The compound of claim 10 wherein L¹—Ar²—Z is structure (II).
 19. Thecompound of claim 18 wherein the R in structure (II) is methoxy.
 20. Thecompound of claim 19 wherein n in structure (II) is
 1. 21. The compoundof claim 20 wherein structure (II) is


22. The compound of claim 21 wherein the compound is:


23. The compound of claim 10 wherein L¹—Ar²—Z is structure (III). 24.The compound of claim 10 wherein L¹—Ar²—Z is structure (IV-a) or (IV-b).25. The compound of claim 24 wherein L¹—Ar²—Z is (IV-a) and both X² instructure (IV-a) are nitrogen.
 26. The compound of claim 25 whereinstructure (IV) is:


27. The compound of claim 26 wherein the compound is:


28. The compound of claim 8 wherein L¹—Ar²—Z is structure (V-a) or(V-b).
 29. The compound of claim 28 wherein L¹—Ar²—Z is structure (V-a)and X² and X³in structure (V-a) are N.
 30. The compound of claim 29wherein at least one R in structure (V) is methyl.
 31. The compound ofclaim 29 wherein X¹ in structure (V) is S.
 32. The compound of claim 31where in structure (V) is:


33. The compound of claim 32 wherein the compound is:


34. The compound of claim 1 wherein both n and p are
 1. 35. The compoundof claim 1 wherein L¹ is CO, CHOH or CH₂.
 36. The compound of claim 35wherein L¹ is CO.
 37. The compound of claim 1 wherein Z¹ is N.
 38. Thecompound of claim 1 wherein Z¹ is CR² wherein R² is H, OR, NR₂, SR orhalo, wherein each R is independently H, alkyl, alkenyl or aryl or theheteroatom-containing forms thereof.
 39. The compound of claim 1 whereinL² is alkylene (1-4C) or alkenylene (1-4C) optionally substituted with amoiety selected from the group consisting of alkyl, alkenyl, alkynyl,aryl, arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl, heteroalkenyl,heteroalkynyl, heteroalkylaryl, NH-aroyl, halo, OR, NR₂, SR, SOR, SO₂R,OCOR, NRCOR, NRCONR₂, NRCOOR, OCONR₂, RCO, COOR, alkyl-OOR, SO₃R, CONR₂,SO₂NR₂, NRSO₂NR₂, CN, CF₃, R₃Si, and NO₂, wherein each R isindependently H, alkyl, alkenyl or aryl or heteroforms thereof, andwherein two substituents on L² can be joined to form a non-aromaticsaturated or unsaturated ring that includes 0-3 heteroatoms which are O,S and/or N and which contains 3 to 8 members or said two substituentscan be joined to form a carbonyl moiety or an oxime, oximeether,oximeester or ketal of said carbonyl moiety.
 40. The compound of claim39 wherein L² is unsubstituted alkylene.
 41. The compound of claim 39wherein L² is unsubstituted methylene, methylene substituted with alkyl,or —CH═.
 42. The compound of claim 1 wherein Ar¹ is optionallysubstituted with 0-5 substituents selected from the group consisting ofalkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl,heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, NH-aroyl,halo, OR, NR₂, SR, SOR, SO₂R, OCOR, NRCOR, NRCONR₂, NRCOOR, OCONR₂, RCO,COOR, alkyl-OOR, SO₃R, CONR₂, SO₂NR₂, NRSO₂NR₂, CN, CF₃, R₃Si, and NO₂,wherein each R is independently H, alkyl, alkenyl or aryl or heteroformsthereof, and wherein two of said optional substituents on adjacentpositions can be joined to form a fused, optionally substituted aromaticor nonaromatic, saturated or unsaturated ring which contains 3-8members.
 43. The compound of claim 42 wherein Ar¹ is optionallysubstituted phenyl.
 44. The compound of claim 43 wherein said optionalsubstitution is by halo, OR, or alkyl.
 45. The compound of claim 44wherein said phenyl is unsubstituted or has a single substituent. 46.The compound of claim 1 wherein R¹ is selected from the group consistingof alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl,heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, NH-aroyl,halo, OR, NR₂, SR, SOR, SO₂R, OCOR, NRCOR, NRCONR₂, NRCOOR, OCONR₂, RCO,COOR, alkyl-OOR, SO₃R, CONR₂, SO₂NR₂, NRSO₂NR₂, CN, CF₃, R₃Si, and NO₂,wherein each R is independently H, alkyl, alkenyl or aryl or heteroformsthereof and two of R⁴ on adjacent positions can be joined to form afused, optionally substituted aromatic or nonaromatic, saturated orunsaturated ring which contains 3-8 members, or R⁴ is ═O or an oxime,oximeether, oximeester or ketal thereof.
 47. The compound of claim 46wherein each R¹ is halo, OR, or alkyl.
 48. The compound of claim 47wherein m is 0, 1, or
 2. 49. The compound of claim 48 wherein m is 2 andboth R¹ are alkyl.
 50. The compound of claim 10 wherein each of thenon-interfering groups R, when bonded to a ring carbon atom, areselected from the group consisting of: (a) hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl,heteroalkenyl, heteroalkynyl, heteroalkylaryl, NH-aroyl and halo; or (b)or from OR, NR₂, SR, SOR, SO₂R, OCOR, NRCOR, NRCONR₂, NRCOOR, OCONR₂,RCO, COOR, alkyl-OOR, SO₃R, CONR₂, SO₂NR₂, NRSO₂NR₂, CN, CF₃, R₃Si, andNO₂, wherein each R in the preceding (b) selections is independently H,alkyl, alkenyl or aryl or heteroforms thereof; and wherein two of thenon-interfering groups R can be joined to form a fused, optionallysubstituted aromatic or nonaromatic, saturated or unsaturated ring whichcontains 3-8 members.
 51. The compound of claim 50 wherein thenon-interfering groups R are independently selected from the groupconsisting of H, alkyl, acyl, aryl, arylalkyl, heteroalkyl, heteroaryl,halo, OR, NR₂, SR, NRCOR, alkyl-OOR, RCO, COOR, and CN, wherein each Ris independently H, alkyl, or aryl or heteroforms thereof.
 52. Thecompound of claim 10 wherein the noninterfering groups R, when bonded toa nitrogen ring atom, are selected from the group consisting of: (a) H,or alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl,heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl; and (b) SOR,SO₂R, RCO, COOR, alkyl-COR, SO₃R, CONR₂, SO₂NR₂, CN, CF₃, or R₃Siwherein each R in the preceding (b) selections is independently H,alkyl, alkenyl or aryl or heteroforms thereof.
 53. A pharmaceuticalcomposition for treating conditions characterized by enhanced p38-αactivity which composition comprises a therapeutically effective amountof a compound of the formula

 and the pharmaceutically acceptable salts thereof, or a pharmaceuticalcomposition thereof, wherein: Ar¹ is an aryl group substituted with 0-5non-interfering substituents, wherein two adjacent noninterferingsubstituents can form a fused aromatic or nonaromatic ring; L¹ and L²are linkers; each R¹ is independently a noninterfering substituent; Z¹is CR² or N wherein R² is hydrogen or a noninterfering substituent; nmis 0-4; each of n and p is an integer from 0-2 wherein the sum of n andp is 0-3; Ar² is a substantially planar, monocyclic or polycyclicaromatic moiety having one or more optional ring heteroatoms, saidmoiety being optionally substituted with one or more non-interferingsubstituents, two or more of which may form a fused ring; Z is—W_(i)—COX_(j)Y wherein Y is COR³ or an isostere thereof, R³ is anoninterfering substituent, each of W and X is a spacer of 2-6 Å, andeach of i and j is independently 0 or 1; wherein the smallest number ofcovalent bonds in the compound separating the atom of Ar¹ bonded to L²to the atom of Ar² bonded to L¹ is at least 6, where each of said bondshas a bond length of 1.2 to 2.0 angstroms; and/or wherein the distancein space between the atom of Ar¹ bonded to L² and the atom of Ar² bondedto L¹ is 4.5-24 angstroms; with the proviso that the portion of thecompound represented by Ar²—Z is not

 wherein

represents a single or double bond; n is 0-3; one Z²is CA or CRA and theother is CR, CR₂, NR or N; A is —W_(i)—COX_(j)Y wherein Y is COR or anisostere thereof, each of W and X is a spacer of 2-6 Å, and each of iand j is independently 0 or 1; Z³ is NR or O; and each R isindependently hydrogen or a noninterfering substituent.
 54. Thepharmaceutical composition of claim 53 wherein said smallest number ofbonds is 6-12.
 55. The composition of claim 53 which further contains anadditional therapeutic agent.
 56. The composition of claim 55 whereinsaid additional therapeutic agent is a corticosteroid, a monoclonalantibody, or an inhibitor of cell division.
 57. A method to treat acondition mediated by p38-α kinase comprising administering to a subjectin need of such treatment a compound of the formula:

and the pharmaceutically acceptable salts thereof, or a pharmaceuticalcomposition thereof, wherein Ar¹ is an aryl group substituted with 0-5non-interfering substituents, wherein two adjacent noninterferingsubstituents can form a fused aromatic or nonaromatic ring; L¹ and L²are linkers; each R¹ is independently a noninterfering substituent; Z¹is CR² or N wherein R² is hydrogen or a noninterfering substituent; m is0-4; each of n and p is an integer from 0-2 wherein the sum of n and pis 0-3; Ar² is a substantially planar, monocyclic or polycyclic aromaticmoiety having one or more optional ring heteroatoms, said moiety beingoptionally substituted with one or more non-interfering substituents,two or more of which may form a fused ring; Z is —W_(i)—COX_(j)Y whereinY is COR³ or an isostere thereof; R³ is a noninterfering substituent,each of W and X is a spacer of 2-6 Å, and each of i and j isindependently 0 or 1; wherein the smallest number of covalent bonds inthe compound separating the atom of Ar¹ bonded to L² to the atom of Ar²bonded to L¹ is at least 6, where each of said bonds has a bond lengthof 1.2 to 2.0 angstroms; and/or wherein the distance in space betweenthe atom of Ar¹ bonded to L² and the atom of Ar² bonded to L¹ is 4.5-24angstroms; with the proviso that the portion of the compound representedby Ar²—Z is not

 wherein

represents a single or double bond; n is 0-3; one Z² is CA or CRA andthe other is CR, CR₂, NR or N; A is —W_(i)—COX_(j)Y wherein Y is COR oran isostere thereof, each of W and X is a spacer of 2-6 Å, and each of iand j is independently 0 or 1; Z³ is NR or O; and each R isindependently hydrogen or a noninterfering substituent.
 58. The methodof claim 57 wherein said smallest number of bonds is 6-12.
 59. Themethod of claim 57 wherein said condition is a proinflammation response.60. The method of claim 59 wherein said proinflammation response ismultiple sclerosis, IBD, rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis, gouty arthritis, other arthritic conditions, sepsis,septic shock, endotoxic shock, Gram-negative sepsis, toxic shocksyndrome, asthma, adult respiratory distress syndrome, stroke,reperfusion injury, CNS injury, psoriasis, restenosis, cerebral malaria,chronic pulmonary inflammatory disease, silicosis, pulmonary sarcosis, abone resorption disease, graft-versus-host reaction, Crohn's Disease,ulcerative colitis, Alzheimer's, pyresis or heart disease.